Increased fatigue resistance linked to Ca2+‐stimulated mitochondrial biogenesis in muscle fibres of cold‐acclimated mice

Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein‐1 (UCP1)‐dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold‐exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild‐type (WT) and UCP1‐ablated (UCP1‐KO) mice kept either at room temperature (24°C) or cold‐acclimated (4°C) for 4–5 weeks. [Ca2+]i (measured with indo‐1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1‐KO mice. However, muscle fibres from cold‐acclimated mice showed significant increases in basal [Ca2+]i (∼50%), tetanic [Ca2+]i (∼40%), and sarcoplasmic reticulum (SR) Ca2+ leak (∼fourfold) as compared to fibres from room‐temperature mice. Muscles of cold‐acclimated mice showed increased expression of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold‐acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations. Prolonged physical exercise leads to increased endurance. This is to a large extent due to skeletal muscle cells becoming better at using oxygen‐dependent metabolism, which occurs in the mitochondria. It is difficult to identify mechanisms behind the training effect because many factors change simultaneously during endurance exercise. For instance, there are changes in energy metabolites and ion concentrations as well as mechanical perturbations. Interestingly, adaptations observed in skeletal muscles of cold‐exposed animals are similar to those observed with endurance training, although with cold exposure the adaptations can occur without changes in metabolites or increased mechanical activity. In this study we show